limantrafin (CB-103) / Cellestia Biotech - LARVOL DELTA

Prolyl-tRNA synthetase inhibition disrupts oncogenic translation in T-cell acute lymphoblastic leukemia (ASH 2025) - "Primary leukemia was then secondary transplanted in wildtype recipients, which were treated with either vehicle or tamoxifen to induce Cre-mediated deletion of Eprs1...These findings were corroborated in vivo , where hemizygous Eprs1 deletion delayed leukemia progression and extended survival. Together, our findings identify enhanced proline tRNA biogenesis as a critical adaptation in T-ALL pathogenesis and provide a strong molecular and preclinical rationale for therapeutically targeting ProRS in T-ALL."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • CCND3 • EPRS1 • HES1 • MYC • NOTCH1

Limantrafin-BODIPY Conjugates Reduce Stemness and Metastatic Potential via Superoxide Driven Phototherapy in Triple Negative Breast Cancer. (PubMed, Small) - "This dual action may impair tumor aggressiveness, recurrence, and promote immunogenic cell death. The findings highlight that the conjugation of the Notch1 inhibitor, Limantrafin, with BODIPY widens the horizon of Type-I photosensitizers to design next-generation PDT agents."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ICAM1 • NOTCH1

CB-103 With Either Lenvatinib or Abemaciclib in Patients With NOTCH ACC (clinicaltrials.gov) - P1/2 | N=32 | Recruiting | Sponsor: Glenn J. Hanna | N=10 ➔ 32 | Active, not recruiting ➔ Recruiting | Trial completion date: Jun 2026 ➔ Jun 2027 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Enrollment change • Enrollment open • Trial completion date • Trial primary completion date • Adenoid Cystic Carcinoma • Oncology

CB-103 With Either Lenvatinib or Abemaciclib in Patients With NOTCH ACC (clinicaltrials.gov) - P1/2 | N=10 | Active, not recruiting | Sponsor: Glenn J. Hanna | Recruiting ➔ Active, not recruiting | N=34 ➔ 10

Enrollment change • Enrollment closed • Adenoid Cystic Carcinoma • Gastrointestinal Cancer • Oncology

Phase II Study to Evaluate Safety and Efficacy of CB-103 With Venetoclax in Adolescent and Young Adult Patients With Relapsed/Refractory T-ALL or T-LBL (clinicaltrials.gov) - P2 | N=2 | Terminated | Sponsor: M.D. Anderson Cancer Center | N=30 ➔ 2 | Trial completion date: Jul 2026 ➔ Aug 2024 | Recruiting ➔ Terminated | Trial primary completion date: Jul 2026 ➔ Aug 2024; The sponsor requested termination due to internal reprioritization of resources.

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • BCL2 • CD2 • CD34 • CD5 • CD7 • CD8

Antimicrobial Peptide Reduces Cytotoxicity and Inflammation in Canine Epidermal Keratinocyte Progenitor Cells Induced by Pseudomonas aeruginosa Infection. (PubMed, Vet Sci) - "The direct effects and antimicrobial activity of synthetic antimicrobial peptides (AMPs) obtained from dogs, including cBD, cBD103, and cCath, against P. aeruginosa wild-type strain PAO1 and canine keratinocytes were analyzed...These results indicate the therapeutic potential of AMPs in P. aeruginosa skin infections. However, further studies on the mechanism of action of AMPs in keratinocytes and clinical trials are needed."

Journal • Dermatology • Infectious Disease • Inflammation • IL6 • TNFA

CB-103 With Either Lenvatinib or Abemaciclib in Patients With NOTCH ACC (clinicaltrials.gov) - P1/2 | N=34 | Recruiting | Sponsor: Glenn J. Hanna | Trial primary completion date: Jun 2024 ➔ Jun 2025

Trial primary completion date • Adenoid Cystic Carcinoma • Gastrointestinal Cancer • Oncology

Unveiling the role of novel carbohydrate-binding modules in laminarin interaction of multimodular proteins from marine Bacteroidota during phytoplankton blooms. (PubMed, Environ Microbiol) - "Exploration of bacterial metagenome-assembled genomes (MAGs) from phytoplankton blooms in the North Sea showed that both laminarin-binding CBM families are widespread among marine Bacteroidota. The high protein abundance of CBM102- and CBM103-containing proteins during phytoplankton blooms further emphasizes their significance in marine laminarin utilization."

Journal

Canine coat color E locus updates: Identification of a new MC1R variant causing 'sable' coat color in English Cocker Spaniels and a proposed update to the E locus dominance hierarchy. (PubMed, Anim Genet) - "We propose calling this newly identified allele e and further show that the e , e and e (previously known as E ) alleles associate with similar phenotypes in dogs impacting genotypes regulated by beta-defensin 103 gene (CBD103; K locus) and agouti signaling protein gene (ASIP; A locus) in the absence of the E and E alleles. This suggests that all three alleles are putative reduced-function variants of the MC1R gene. We propose the revised and updated E locus dominance hierarchy to be E  > E > e /e /e  > e ."

Journal • MC1R

CAILA: CB-103 Plus NSAI In Luminal Advanced Breast Cancer (clinicaltrials.gov) - P2 | N=2 | Terminated | Sponsor: MedSIR | N=80 ➔ 2 | Active, not recruiting ➔ Terminated; Sponsor decision

Enrollment change • Metastases • Trial termination • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

White and other fur colourations and hybridization in golden jackals (Canis aureus) in the Carpathian basin. (PubMed, Sci Rep) - "Sequences and fragment length polymorphisms were studied for white colour (MC1R), and for black coat colouration (CBD103)...Kinship was found three times, twice between white animals, and once between a white animal and an agouti animal carrying the mutation of white coat. Our results confirm the findings that golden jackal-dog hybrids may occur without human intervention, and the detected mutation causing white fur colour in golden jackals could possibly be due to an early hybridization event."

Journal

A Phase I Study of the Pan-Notch Inhibitor CB-103 for Patients with Advanced Adenoid Cystic Carcinoma and Other Tumors. (PubMed, Cancer Res Commun) - "Peripheral downregulation of select Notch target gene levels was observed with escalating doses. Future studies exploring CB-103 should enrich for patients with NOTCH-mutant ACC and investigate rational combinatorial approaches in tumors where there is limited success with investigational or approved drugs."

Journal • Metastases • P1 data • Adenoid Cystic Carcinoma • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • NICD

Evaluation of the anticancer activity of RIN-1, a Notch signaling modulator, in head and neck squamous cell carcinoma. (PubMed, Sci Rep) - "Here, we present the growth- and differentiation-modulating effects of various "next generation" small molecule Notch modulators represented by RIN-1, and CB-103, on HNSCC, compared to gamma secretase inhibitors as "conventional" NOTCH interfering compounds, like DAPT...In contrast, RIN-1 treatment resulted in inhibition of Notch signalling and the growth of HNSCC spheroids under non-adherent cell culture conditions. Our results suggest that modulation of Notch signalling could be used as a chemotherapeutic agent in selected patients with intact NOTCH signaling."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CDKN1A • HES1 • HEY1

The Efficacy of CB-103, a First-in-Class Transcriptional Notch Inhibitor, in Preclinical Models of Breast Cancer. (PubMed, Cancers (Basel)) - "our data indicate that CB-103 is an attractive candidate for clinical investigation in endocrine-resistant, recurrent breast cancers with biomarker-confirmed Notch activity in combination with SERDs and/or CDKis and in TNBCs with biomarker-confirmed Notch activity in combination with taxane-containing chemotherapy regimens."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER

Research suggests a new approach for treatment-resistant breast cancers (Medical Xpress) - "A collaborative study between LSU Health New Orleans School of Medicine, the University of Rochester and Cellestia Biotech AG, a biopharmaceutical company headquartered in Basel, Switzerland, provides compelling evidence that combining an investigational oral drug with standard-of-care medications reverts hormone resistance and increases Rx effectiveness in experimental models of estrogen-receptor positive (ER+) and triple-negative breast cancers (TNBC), respectively...CB-103 is a small molecule Notch inhibitor invented by Cellestia....Based on their prior research, the LSU Health team believed this compound should be safe and effective in hormone-resistant estrogen-receptor-positive breast cancers and proposed the study for this indication to Cellestia."

Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Effect of Allergen-Specific Immunotherapy on Transcriptomic Changes in Canine Atopic Dermatitis. (PubMed, Int J Mol Sci) - "Based on the available literature, we chose nine differentially expressed genes (RARRES2, DPP10, SLPI, PLSCR4, MMP9, NTSR1, CBD103, DEFB122, and IL36G) which may be important in the context of the dysregulated immune response observed in cAD patients...The expressions of three of these genes returned to the level observed in the healthy control group. The genes listed above need further investigation to determine details of their role in the molecular mechanism of immune tolerance induction in response to allergen-specific immunotherapy."

IO biomarker • Journal • Allergy • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • MMP9 • RARRES2

[PREPRINT] The efficacy of CB-103, a first-in-class transcriptional Notch inhibitor, in preclinical models of breast cancer (bioRxiv) - "CB-103 showed synergism with fulvestrant in ER+ cells and with paclitaxel in TNBC cells. CB-103 combined with fulvestrant or paclitaxel potently inhibited mammosphere formation in both models. Combination of CB-103 and fulvestrant significantly reduced tumor volume in an ESR1-mutant, endocrine-resistant BC model. In a GSI-resistant TNBC model, CB-103 plus paclitaxel significantly delayed tumor growth compared to paclitaxel alone."

Preclinical • Preprint • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

A Phase 1/2 Study CB-103 With or Without Venetoclax in Patients With NOTCH ACC (clinicaltrials.gov) - P1/2 | N=34 | Recruiting | Sponsor: Glenn J. Hanna | Not yet recruiting ➔ Recruiting

Enrollment open • Adenoid Cystic Carcinoma • Gastrointestinal Cancer • Oncology • BCL2

Metastatic clear-cell renal cell carcinoma: a frequent NOTCH1 mutation predictive of response to anti-NOTCH1 CB-103 treatment. (PubMed, Exp Hematol Oncol) - "We identified a frequent, unexpected pL1575P_c4724T_C NOTCH1 mutation as a new biomarker for ccRCC metastases, predictive of response to the CB103 NOTCH1-intracellular domain inhibitor."

Journal • Metastases • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • NICD • NOTCH1

Phase II Study to Evaluate Safety and Efficacy of CB-103 With Venetoclax in Adolescent and Young Adult Patients With Relapsed/Refractory T-ALL or T-LBL (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting | Initiation date: Dec 2023 ➔ Apr 2023

Combination therapy • Enrollment open • Trial initiation date • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • BCL2 • CD2 • CD34 • CD5 • CD7 • CD8

"Excited to bring new agents to our Pediatric T cell program at MDA. CB-103 + Venetoclax is now active and enrolling children. Congrats Dr.Garcia! @GBorthakur @MDAndersonNews https://t.co/z1ltejo5hw" (@CuglievanBranko)

Clinical • Pediatrics

A Phase 1/2 Study CB-103 With or Without Venetoclax in Patients With NOTCH ACC (clinicaltrials.gov) - P1/2 | N=34 | Not yet recruiting | Sponsor: Glenn J. Hanna

New P1/2 trial • Adenoid Cystic Carcinoma • Gastrointestinal Cancer • Oncology • BCL2

Phase II Study to Evaluate Safety and Efficacy of CB-103 With Venetoclax in Adolescent and Young Adult Patients With Relapsed/Refractory T-ALL or T-LBL (clinicaltrials.gov) - P2 | N=30 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center | Initiation date: Dec 2022 ➔ Dec 2023

Trial initiation date • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • BCL2 • CD2 • CD34 • CD5 • CD7 • CD8

Study of CB-103 in Adult Patients With Advanced or Metastatic Solid Tumours and Haematological Malignancies (clinicaltrials.gov) - P1/2 | N=79 | Terminated | Sponsor: Cellestia Biotech AG | N=200 ➔ 79 | Recruiting ➔ Terminated; business reason

Enrollment change • Metastases • Trial termination • Acute Lymphocytic Leukemia • Adenoid Cystic Carcinoma • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Hepatocellular Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • T Acute Lymphoblastic Leukemia • Triple Negative Breast Cancer • HER-2

"our work on in vitro targeting NOTCH in #lymphoma with ⁦@CellestiaBio⁩ CB-103 is out. ⁦@IOR_Bellinzona⁩ ⁦@USI_en⁩ ⁦@EnteOspedaliero⁩ ⁦@AnastasiosStat2⁩ ⁦@CascioneLuciano⁩ https://t.co/IwqYQSVKVQ" (@frbertoni)

Preclinical • Hematological Malignancies • Lymphoma • Oncology